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Confronting Acquired Resistance in Brain Tumors

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“Despite their ability to induce dramatic tumor responses with fewer side effects, the effectiveness of targeted therapies is currently limited because the majority of patients using these agents develop resistance over time, resulting in a relapse or worsening of the cancer” – A post on the website of Massachusetts General Hospital in Fall, 2011

The issue of “acquired resistance” has become a much-discussed topic in recent years within the oncology field.

This is one of the single biggest challenges in treating brain tumors.

Cancer Today recently published an informative article on how “acquired resistance” happened in tumors. The article, titled “Why Cancer Drugs Stop Working in Some Patients,” quotes Dr. Charles Sawyers, MD, of Memorial Sloan Kettering Cancer Center, and the immediate past president of the American Association for Cancer Research:

“We’ve become extremely good at making drugs that inhibit many of the cancer-driving genes,” Dr. Sawyers said. “We are killing more tumor cells with new drugs, but there are some [left-over] cells that are looking for a backdoor” to continue growing. “[The cancer then says,] ‘I’m going to change…into something else’. It’s changed its identity.”

The highlighted portion of Dr. Sawyers quote speaks to how tumor cells are able to adapt, and use different mechanisms than they were originally using to continue growing. Thus, the drug that was being given as a treatment – which had specifically been designed to target and inhibit the original mechanism – is no longer effective. This, is why some cancer drugs stop working in some patients.

While, drug resistance is a challenge for all tumors and cancer, it is especially difficult for very aggressive and complex tumors like many malignant brain tumors.

One of the possible prescriptions Dr. Sawyers notes for overcoming the resistance problem in cancer, is for researchers from across the country to work together and share their data and knowledge to help understand how tumor cells develop resistance.

This was part of the rationale that the National Brain Tumor Society had in mind when we developed the Defeat GBM Research Collaborative.

Defeating Resistance in GBM

One of Defeat GBM’s four complementary projects, the Discovery effort – led by Ludwig Cancer Research scientists Dr. Webster Cavenee and Dr. Frank Furnari – aims, specifically, to identify and target the ‘escape and evade’ methods GBM cells use to develop resistance.

Blog_DefeatGBM_logo_565x274The scientists working in the Defeat GBM Research Collaborative held one of their regular check-in calls earlier in April, and it was the Discovery team from Ludwig’s turn to give the full group an overview on their current progress.

The Ludwig team is targeting EGFR, as well as other well-characterized GBM mutations.  Their goal is to find out after they inhibit targets like EFGR (which is over-expressed in many GBM tumors), what new mutations the tumor cells use to continue you growing. Once these so-called resistance mechanisms are known, a combination therapy could be used both inhibit the tumors initial mutations, as well as its subsequent escape route.

One of the National Brain Tumor Society’s Strategic Scientific Advisors, Dr. Anna Barker, is a co-director of a program at Arizona State University called the “Complex Adaptive Systems Initiative.” This is a perfect name for the study of many cancers, like malignant brain tumors. Tumor cells are not just complex, but they also are able to adapt and use a system of interrelated pathways to continue to grow even as today’s best medicines are being applied.

We hope for a future where a combination of new, or existing drugs can be identified and utilized to overcome resistance. And Programs like our Defeat GBM Research Collaborative aim to do just that.

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